Two types of adipose tissue can be distinguished which have very distinct features and functions: white adipose tissue (WAT) storing energy primarily as triglycerides in distinct anatomical locations and brown adipose tissue (BAT) specialized in basal and inducible energy expenditure through heat production. BAT and WAT are distinct anatomically, histologically and functionally. Until recently, brown adipose tissue (BAT) was considered of metabolic significance only in small mammals and human newborns, since it was thought to disappear rapidly after birth in humans. However, functional brown adipose tissue has been identified and characterized in adult humans promoting a renewed interest in non-shivering thermogenesis and development of future perspectives targeting BAT for pharmacological treatment of obesity and metabolic diseases.
The last decade has witnessed a profound resurgence in BAT research with a clear adult human emphasis. The need for such a dramatic increase stems from the ever-growing trend toward global human obesity. Indeed, it is currently estimated that rates of obesity in developed countries such as the United States exceed 35% of the population (Flegal, et al 2010). The higher incidence of obesity is associated with increased prevalence of the Metabolic Syndrome including diabetes, hypertension, and coronary heart disease, among others (Alberti, et al 2009, Bruce and Hanson 2010). BAT holds great promise in combating obesity given its unprecedented metabolic capacity. Although several early anatomical studies suggested that brown adipose tissue is present in adult humans (Astrup, et al 1985), its physiologic relevance was believed to be marginal. Recent controlled studies showed that functional BAT is detectable in lean, obese and morbidly obese adult humans after exposure to mild cold (Saito, et al 2009, van Marken Lichtenbelt, et al 2009, Vijgen, et al 2011, Virtanen, et al 2009). Cold induced BAT activity is inversely related to body mass index (BMI) and body fat percentage (BF %) (van Marken Lichtenbelt, et al 2009, Saito, et al 2009, Virtanen, et al 2009, Yoneshiro, et al., Obesity, Vol. 19, No. 1, January 2011). Two types of brown fat cells have been reported: brown fat cells originating from a Myf5+ progenitor cells common to muscle cells and as exemplified by brown fat cells in classic locations such as interscapular, and brown fat cells interspersed in WAT which are derived from another lineage and could arise from either a dormant precursor cell or transdifferentiation from white fat (Perwitz, et al 2010, Seale, et al 2008).
The thermogenic phenotype of BAT is essentially conferred by uncoupling protein 1 (UCP1). UCP1 uncouples adenosine-5′-triphosphate (ATP) synthesis from substrate oxidation in brown adipocytes.
Brown adipose tissue (BAT) is the major site for cold- and diet-induced thermogenesis, which significantly contributes to control of the body temperature and energy expenditure, at least in small rodents such as the mouse, rat, and hamster (Cannon and Nedergaard 2004), (Klingenspor 2003), (Himms-Hagen 1990). In humans, BAT is present in newborns, but disappears rapidly during postnatal periods and, in adults, is rather difficult to identify by conventional anatomical examinations.
Brown adipose tissue has a very high uptake of glucose per gram of tissue, which means that even though the total amount of brown adipose tissue in the body is not large, it can potentially be a significant glucose-clearing organ. Physiological conditions in which plasma insulin levels are elevated show increased glucose uptake into brown adipose tissue. Brown adipose tissue is one of the most insulin-responsive tissues with respect to stimulation of glucose uptake (Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance; Physiol Rev 84: 277-359, 2004) Because of the importance of brown adipose tissue as a sink for glucose uptake, BAT manipulation opens new opportunities for the development of new therapeutics for metabolic diseases such as obesity and type-2 diabetes (Kajimura et al., Nature 460, 1154-1158., 2009).
It has been discovered that formation and/or activity of thermogenic brown adipocytes was increased in white fat tissue of mice treated with an ActRIIB antagonists (WO2010144452). However, it has also been discovered that treatment with ActRIIB antagonists, for example, soluble ActRIIB proteins causes statistically significant hematological changes, including elevated reticulocyte levels and red blood cell distribution width values. Excessive increases in red blood cell levels or cell width, hemoglobin levels, or hematocrit levels may (i) cause increases in blood pressure, (ii) slow down blood velocity, and (iii) increase the risk of sludging, thrombosis or stroke. Consequently, it has been recommended to restrict dosing of ActRIIB antagonists to patients who have appropriate hematologic parameters or patients that have both anemia and muscle loss (WO/2009/158025). Additionally, a method of managing patients treated with an ActRIIB antagonist, comprising monitoring hematologic parameters that correlate with increased red blood cell levels has been developed (WO/2009/158025). Consequently, there is a need to develop novel methods for the treatment of metabolic disorders like Metabolic Syndrome, obesity, insulin resistance, Type 2 Diabetes mellitus and/or increasing brown adipose tissue (BAT) in a patient while not inducing significant hematological changes in said subject.